Project summary Breast cancer (BCa) is the second leading cause of cancer death in women. Among Servicewomen, BCa is the most commonly diagnosed cancer, accounting for 30% of female cancers with increased prevalence in older Veterans. BCa has distinct molecular subtypes; estrogen receptor (ER) positive and triple negative breast cancer (TNBC). A significant portion of ER-positive BCa initially respond to anti-estrogens or aromatase inhibitors but eventually exhibit unresponsiveness to therapy, develop therapy-resistant breast cancer (TR-BC), and ultimately progress to incurable metastasis. Moreover, TNBC has a more aggressive clinical course and overall lack of targeted therapies. Development of effective therapies for female Veterans with TR-BC or TNBC represents the highest unmet need in breast cancer treatment. Our ongoing research on PELP1, an oncogenic coregulator protein originally cloned in this lab, displays an integral role in multiple nuclear receptor (NR) functions associated with BCa progression. PELP1 expression is commonly dysregulated in BCa eliciting a conducive environment for epigenetic modifications. Concomitantly, PELP1 is a prognostic indicator for poorer BCa survival and indicator of therapy resistance and metastases. We have developed a first-in-class small molecule inhibitor of PELP1 (SMIP) displaying effectivity against TR-BC and TNBC. SMIPs block PELP1?s ability to promote epigenetic modifications. The objective of this proposal is to further develop a lead SMIP into a novel drug for the clinical treatment of TR-BC and TNBC. Our overarching hypothesis is that PELP1 couples NRs with epigenetic modifiers; therefore, targeting the PELP1 axis with SMIPs will have a therapeutic utility in treating both TR-BC and TNBC. In Aim 1, we will determine lead SMIPs mechanism of action using biochemical, molecular, unbiased mass spectroscopy, and whole genome sequencing approaches. In Aim 2, we will optimize SMIP derivatives and conduct studies establishing the maximum tolerated dose and dose efficacy in vivo using TR-BC and TNBC models. In Aim 3, we will test the translatability of optimized SMIPs using therapy resistant xenografts, metastatic models, and patient derived xenografts (PDX). This proposal is innovative as SMIPs block signaling from multiple oncogenic PELP1 activated NRs to uniquely promote repression of epigenetic modifiers. Successful completion of the proposed work will result in the development of a first-in-class cancer therapy drug specifically addressing the current lack of TR-BC and TNBC targeted therapies. This research program is significant as it is expected to aid in identifying therapeutic targets critical to the treatment and prevention of advanced breast cancer in the population of Servicewomen.